The phenomenon of cellular adhesion plays an important role in the complex processes of inflammation and cancer metastasis. In response to injury and infection, damaged tissues release activating factors known as cytokines. The released cytokines signal vascular endothelial cells to change their shape and express cell adhesion proteins called selectins on their surfaces. The selectins promote the adhesion of leukocytes to the endothelium by binding to carbohydrate antigens, such as sialyl Lex, that are present on the surface of leukocytes in the blood stream. The leukocytes then move past the endothelial cells, through the blood vessel wall, and into the areas of injury and infection, thereby establishing a foci of inflammation.
In certain situations, adhesion of leukocytes to the endothelium may be abnormal or excessive, resulting in tissue damage instead of repair. A number of inflammatory diseases and related disorders are characterized by aberrant cellular adhesion, including atherosclerosis, blood clotting, rheumatism, arthritis, psoriasis, dermatitis, cancer, reperfusion injuries, and infection. Thus, there is a need for inhibitors of the adhesion process that are capable of alleviating the symptoms associated with such conditions.
Analogs of sialyl Lex that exhibit enhanced binding characteristics to selectins are believed to block the leukocyte adhesion process and prevent the penetration of leukocytes into the injury site, thereby reducing or eliminating the symptoms associated with inflammation. Recent efforts have been made to develop SLex analogs with improved binding properties. The binding of monomeric SLex analogs to E-selectin and L-selectin is generally weak (i.e. only in the range of 1-2 mm), often making them unsuitable for many applications, including targeting. The binding of bridged, dimeric sialyl Lex analogs, however, was reported to be about 5 fold greater than the monomer, depending upon the nature of the bridge connecting the two monomers. Multivalent liposomic sialyl Lex mimetics have been shown to exhibit up to a 100 fold greater binding strength than controls in selectin-mediated cell adhesion inhibition assays. Furthermore, a sialyl Lex-PEG-DSPE derivative that was incorporated into PEG grafted liposomes was shown to be greater than 5000 fold more potent than the monomeric analog as an inhibitor of E-selectin mediated cellular adhesion in an ELISA assay.